KR20130127993A - Process for the preparation of aromatic thiol derivatives by hydrogenation of disulfides - Google Patents

Abstract

The present application relates to the preparation of thiophenols by reacting a corresponding disulfide with hydrogen in the presence of a heterogeneous transition metal hydrogenation catalyst. When the reaction is carried out in the presence of acylating agents such as carboxylic anhydrides or halides, acylated thiophenols are obtained. A pharmaceutically active compound, S- [2- [1- (2-ethylbutyl) -cyclohexylcarbonylamino] -phenyl] 2-methylthiopropionate, is produced via this method.

Description

Process for producing aromatic thiol derivative by hydrogenation of disulfide {PROCESS FOR THE PREPARATION OF AROMATIC THIOL DERIVATIVES BY HYDROGENATION OF DISULFIDES}

The present invention relates to a process for preparing S- [2- [1- (2-ethylbutyl) cyclohexylcarbonylamino] -phenyl] 2-methylthiopropionate, which is a useful pharmaceutically active compound.

S- [2-([[1- (2-ethylbutyl) cyclohexyl] carbonyl] amino) phenyl] 2-methylpropanethioate is described in human (de Grooth et al., Circulation, 105, 2159-2165 (2002))) and rabbits (Shinkai et al., J. Med. Chem., 43, 3566-3572 (2000)), Kobayashi et al., Atherosclerosis, 162, 131-135 (2002)] And Okamoto et al., Nature, 406 (13), 203-207 (2000), have been shown to be inhibitors of cholesterol ester transfer protein (CETP) activity. S- [2-([[1- (2-ethylbutyl) cyclohexyl] carbonyl] amino) phenyl] 2-methylpropanethioate is human (de Grooth et al., Supra) and rabbit (document Shinkai et al., Supra, Kobayashi et al., Supra and Okamoto et al., Supra) have been shown to increase plasma high density lipoprotein (HDL) cholesterol. In addition, S- [2-([[1- (2-ethylbutyl) cyclohexyl] carbonyl] amino) phenyl] 2-methylpropanethioate is used in humans (de Grooth et al., Supra) and rabbits. (Okamoto et al., Supra) have been shown to reduce low density lipoprotein (LDL) cholesterol. In addition, S- [2-([[1- (2-ethylbutyl) cyclohexyl] carbonyl] amino) phenyl] 2-methylpropanethioate inhibits the progression of atherosclerosis in rabbits ( Okamoto et al., Supra).

In a first embodiment, the present invention provides a process for the preparation of a compound of formula I '', comprising reacting a compound of formula II '' with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst:

Formula I ''

[In the above formula,

X ¹ , X ² , X ³ and X ⁴ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH -C (= 0) R ^d or -NR ^e ₂ ;

Two adjacent substituents (ie, X ¹ and X ² , or X ² and X ³ , or X ³ and X ⁴ ) optionally include additional heteroatoms selected from O, NH and S together with the carbon atoms to which they are attached To form a 4, 5 or 6 membered cycloalkyl ring, wherein the above mentioned 4, 5 or 6 membered cycloalkyl ring is optionally substituted with 1 to 3 substituents independently selected from (C ₁ -C ₈ ) alkyl or aryl Become;

R ^a , R ^b , R ^c and R ^d are independently (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, aryl or heteroaryl;

Each R ^e is independently hydrogen, (C ₁ -C ₈ ) alkyl or aryl.]

Formula II ''

[In the above formula,

X ^{1 ′} , X ^{2 ′} , X ^{3 ′} and X ^{4 ′} are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH-C (= 0) R ^d or -NR ^e ₂ ;

Two adjacent substituents (ie, X ^{1 ′} and X ^{2 ′} , or X ^{2 ′} and X ^{3 ′} , or X ^{3 ′} and X ^{4 ′} ) together with the carbon atoms to which they are attached are further selected from O, NH and S To form a 4, 5 or 6 membered cycloalkyl ring optionally containing heteroatoms, wherein the above mentioned 4, 5 or 6 membered cycloalkyl ring is selected from 1 to 3 independently selected from (C ₁ -C ₈ ) alkyl or aryl Optionally substituted with 4 substituents;

R ^a , R ^b , R ^c , R ^d , R ^e , X ¹ , X ² , X ³ and X ⁴ are as defined above.]

To date, conventional disulfide reduction methods cause similar drawbacks. They use stoichiometric amounts of reducing agents, large amounts of waste and / or heavy work-ups that cause safety problems. At the laboratory scale, these drawbacks may not seem to matter much, but as they move to mass production, they are carefully observed due to factorial effects.

SS disulfide bonds (and SH bonds formed during the hydrogenation process) are considered catalytic poisons due to the strong chemisorption of sulfur-containing molecules on metal surfaces (Houben-Weyl, Methoden der Organischen Chemie, Band IV / 1c, published). 1980, page 486 or F. Zymalkowski, Katalytische Hydrierungen im Organisch-Chemischen Laboratorium, F. Enke Verlag Stuttgart, published 1965, page 37). Thus, it has surprisingly been found that the reduction of disulfide bonds according to the invention is selective with high throughput.

The present invention does not require pretreatment of the catalyst, in particular sulfide pretreatment of the catalyst.

Unless stated otherwise, the following terms used in the specification and claims have the meanings given below:

The term "halo" or "halide" means fluoro, chloro, bromo or urethra, in particular chloro or bromo.

The term “(C ₁ -C ₈ ) alkyl” refers to a branched or straight chain hydrocarbon of 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- Butyl, ethyl-butyl, pentyl, hexyl, heptyl and octyl.

The term “(C ₁ -C ₈ ) alkoxy” means a moiety of the formula —OR ^ab , wherein R ^ab is a (C ₁ -C ₈ ) alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

The term "(C ₃ -C ₈ ) cycloalkyl" denotes a single saturated carbocyclic ring of 3 to 8 ring carbons, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl may optionally be substituted with one or more substituents, preferably one, two or three substituents. Preferably, the cycloalkyl substituent is (C ₁ -C ₈ ) alkyl, hydroxy, (C ₁ -C ₈ ) alkoxy, halo (C ₁ -C ₈ ) alkyl, halo (C ₁ -C ₈ ) alkoxy, halo , Amino, mono- and di (C ₁ -C ₈ ) alkylamino, hetero (C ₁ -C ₈ ) alkyl, acyl, aryl and heteroaryl.

"Aryl" is optionally each independently selected from (C ₁ -C ₈ ) alkyl, hydroxy, (C ₁ -C ₈ ) alkoxy, amino, mono- and di (C ₁ -C ₈ ) alkylamino, carboxy, (C ₁ -C ₈ ) alkylsulfonyl, -SO ₂ -aryl, -SO ₃ H, -SO _3- (C ₁ -C ₈ ) alkyl and -SO ₂ -NR ^ac ₂ , wherein R ^ac is independently Monovalent monocyclic or bicyclic aromatic hydrocarbon residues substituted with one or more, preferably one, two or three substituents selected from the group consisting of hydrogen or (C ₁ -C ₈ ) alkyl. More particularly, the term aryl includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like, each of which may or may not be substituted.

"Heteroaryl" refers to a group of 5 to 12 ring atoms containing one, two or three ring heteroatoms selected from N, O or S (preferably N or O) and having at least one aromatic ring having the remaining ring atom C; By monovalent monocyclic or bicyclic moiety it is understood that the point of attachment of the heteroaryl moiety is an aromatic ring. Heteroaryl rings may be optionally one or more of each independently selected from (C ₁ -C ₈ ) alkyl, halo (C ₁ -C ₈ ) alkyl, hydroxy, (C ₁ -C ₈ ) alkoxy, halo, nitro and cyano Substituents are preferably substituted independently with 1, 2 or 3 substituents. More particularly, the term heteroaryl refers to pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetra Hydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindoleyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimi Dazolyl, benzisoxazolyl or benzothienyl, imidazo [1,2-a] pyridinyl, imidazo [2,1-b] thiazolyl and derivatives thereof.

"Heterogeneous transition metal hydrogenation catalyst" refers to a transition metal hydrogenation catalyst that acts in a different phase than the substrate. In particular, the transition metal hydrogenation catalyst is a solid phase. In particular, while the transition metal hydrogenation catalyst is in solid phase, the reactants are in liquid phase. Transition metal hydrogenation catalysts form one or more stable ions with partially filled d orbitals (ie, Pd, Pt, Rh, Au, Ni, Co, Ru, Ir), especially precious metals such as Pd, Pt, Rh or Au. It contains a transition metal. In such a catalyst, the transition metal is in particular "supported", meaning that the catalyst is dispersed on a second metal which enhances the effect. A "support" may be a surface on which only metal spreads to increase the surface area. The support is a porous metal with high surface area, most commonly alumina or various kinds of carbon. Examples of additional supports include, but are not limited to, silicon dioxide, titanium dioxide, calcium carbonate, barium sulfate, diatomaceous earth, and clay. If no other support is present, the metal itself may also serve as the support. More particularly, the term “heterogeneous transition metal hydrogenation catalyst” refers to Raney catalysts (eg Ra-Ni, Ra-Co), Pd / C, Pd (OH) ₂ / C, Au / TiO ₂ , Rh / C , Ru / Al ₂ O _{3 ,} Ir / CaCO ₃ or Pt / C. In certain embodiments, the term "heterogeneous transition metal hydrogenation catalyst" is not pretreated with sulfides.

"Area%" for Substance A represents (area of Substance A) / (sum of all peak areas) × 100 and the area is obtained from HPLC or GC analysis.

In particular, chemical groups having the definitions given above are specifically illustrated in the Examples.

Unless stated otherwise, all percentages are given in weight percent of the total weight of the compound of formula (I).

In a second embodiment, the invention relates to acylating agents such as anhydride derivatives [((C ₁ -C ₈ ) alkyl) C (= 0)] ₂ O or [aryl (C = 0)] ₂ O, or halide derivatives ( Reacting a compound of formula II 'with H _{2 in} the presence of a (C ₁ -C ₈ ) alkyl) C (═O) halide or aryl (C═O) halide and a heterogeneous transition metal hydrogenation catalyst, There is provided a process for the preparation of a compound of formula I '''

Formula I '' '

[In the above formula,

X ¹ , X ² , X ³ and X ⁴ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH -C (= 0) R ^d or -NR ^e ₂ ;

Two adjacent substituents (ie, X ¹ and X ² , or X ² and X ³ , or X ³ and X ⁴ ) optionally include additional heteroatoms selected from O, NH and S together with the carbon atoms to which they are attached To form a 4, 5 or 6 membered cycloalkyl ring, wherein the above mentioned 4, 5 or 6 membered cycloalkyl ring is optionally substituted with 1 to 3 substituents independently selected from (C ₁ -C ₈ ) alkyl or aryl Become;

R ¹ is (C ₁ -C ₈ ) alkyl or aryl;

R ^a , R ^b , R ^c and R ^d are independently (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, aryl or heteroaryl;

Each R ^e is independently hydrogen, (C ₁ -C ₈ ) alkyl or aryl.]

Formula II ''

[In the above formula,

X ^{1 ′} , X ^{2 ′} , X ^{3 ′} and X ^{4 ′} are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH-C (= 0) R ^d or -NR ^e ₂ ;

Two adjacent substituents (ie, X ^{1 ′} and X ^{2 ′} , or X ^{2 ′} and X ^{3 ′} , or X ^{3 ′} and X ^{4 ′} ) together with the carbon atoms to which they are attached are further selected from O, NH and S To form a 4, 5 or 6 membered cycloalkyl ring optionally containing heteroatoms, wherein the above mentioned 4, 5 or 6 membered cycloalkyl ring is selected from 1 to 3 independently selected from (C ₁ -C ₈ ) alkyl or aryl Optionally substituted with 4 substituents;

R ^a , R ^b , R ^c , R ^d , R ^e , X ¹ , X ² , X ³ and X ⁴ are as defined above.]

In another embodiment, the present invention provides a process for preparing a compound of formula I '', comprising reacting a compound of formula II '' with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst:

Formula I ''

[In the above formula,

X ¹ is -NH-C (= O) R d, wherein R ^d is (C ₁ -C ₈₎ alkyl substituted with (C ₃ -C ₈₎ cycloalkyl, in particular (2-ethyl-butyl) cycloalkyl Hexyl;

X ² , X ³ and X ⁴ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH-C ( = O) R ^d or -NR ^e ₂ , especially each independently hydrogen or (C ₁ -C ₈ ) alkyl;

R ^a , R ^b , R ^c and R ^d are independently (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, aryl or heteroaryl;

Each R ^e is independently hydrogen, (C ₁ -C ₈ ) alkyl or aryl.]

Formula II ''

[In the above formula,

X ^{1 '} is -NH-C (= 0) R ^d or -NR ^e' ₂ ;

R ^d is (C ₃ -C ₈ ) cycloalkyl, in particular (2-ethyl-butyl) -cyclohexyl, substituted with (C ₁ -C ₈ ) alkyl;

R ^{e '} is hydrogen;

X ^{2 '} , X ^3' and X ^{4 '} are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH -C (= 0) R ^d or -NR ^e ₂ , especially each independently hydrogen or (C ₁ -C ₈ ) alkyl;

R ^a , R ^b , R ^c , R ^d , R ^e , X ¹ , X ² , X ³ and X ⁴ are as defined above.]

In another embodiment, the present invention provides a process for preparing a compound of formula I ''', comprising reacting a compound of formula II''with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst. :

Formula I '' '

[In the above formula,

X ¹ is -NH-C (= O) R d, wherein R ^d is (C ₁ -C ₈₎ alkyl substituted with (C ₃ -C ₈₎ cycloalkyl, in particular (2-ethyl-butyl) cycloalkyl Hexyl;

X ² , X ³ and X ⁴ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH-C ( = O) R ^d or -NR ^e ₂ , especially each independently hydrogen or (C ₁ -C ₈ ) alkyl;

R ^a , R ^b , R ^c and R ^d are independently (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, aryl or heteroaryl;

Each R ^e is independently hydrogen, (C ₁ -C ₈ ) alkyl or aryl;

R ¹ is (C ₁ -C ₈ ) alkyl or aryl.]

Formula II ''

[In the above formula,

X ^{1 '} is -NH-C (= 0) R ^d or -NR ^e' ₂ ;

R ^d is (C ₃ -C ₈ ) cycloalkyl, in particular (2-ethyl-butyl) -cyclohexyl, substituted with (C ₁ -C ₈ ) alkyl;

R ^{e '} is hydrogen;

X ^{2 '} , X ^3' and X ^{4 '} are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH -C (= 0) R ^d or -NR ^e ₂ , especially each independently hydrogen or (C ₁ -C ₈ ) alkyl;

R ^a , R ^b , R ^c , R ^d , R ^e , X ¹ , X ² , X ³ and X ⁴ are as defined above.]

In a further embodiment, the present invention provides a process for preparing a compound of formula (I ') comprising reacting a compound of formula (II') with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst:

(I ')

Formula II ''

Where

이다.R is H or

to be.

In a further embodiment, the present invention provides a process for preparing a compound of formula (I ') and (X), comprising reacting a compound of formula (II') with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst. do:

≪ RTI ID =

(X)

[Formula II ']

Where

이다.R is H or

to be.

In another embodiment, the present invention provides a process for the preparation of compounds of formula (I ') and (X), comprising reacting a compound of formula (II) with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst. :

≪ RTI ID =

X

≪ RTI ID = 0.0 &

In another embodiment, the present invention provides a process for preparing a compound of formula I ', comprising reacting a compound of formula II with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst:

≪ RTI ID =

(II)

In another embodiment, the invention provides acylating agents such as anhydride derivatives [((C ₁ -C ₈ ) alkyl) C (= 0)] ₂ O or [aryl (C = 0)] ₂ O, or halide derivatives ( Reacting a compound of formula II 'with H _{2 in} the presence of a (C ₁ -C ₈ ) alkyl) C (═O) halide or aryl (C═O) halide and a heterogeneous transition metal hydrogenation catalyst, Provided is a process for the preparation of the compound of formula la. In particular, when the following R ¹ is isopropyl, the acylating agent is isobutyric anhydride or isobutyryl halide, in particular isobutyric anhydride:

(Ia)

[In the above formula,

R ¹ is (C ₁ -C ₈ ) alkyl or aryl, especially isopropyl.]

Formula II ''

[In the above formula,

이다.]R is H or

to be.]

In another embodiment, the invention provides acylating agents such as anhydride derivatives [((C ₁ -C ₈ ) alkyl) C (= 0)] ₂ O or [aryl (C = 0)] ₂ O, or halide derivatives ( Reacting a compound of formula II 'with H _{2 in} the presence of a (C ₁ -C ₈ ) alkyl) C (═O) halide or aryl (C═O) halide and a heterogeneous transition metal hydrogenation catalyst, Provided are methods for preparing compounds of Formula (la) and (X). In particular, when the following R ¹ is isopropyl, the acylating agent is isobutyric anhydride or isobutyryl halide, in particular isobutyric anhydride:

Ia

[In the above formula,

R ¹ is (C ₁ -C ₈ ) alkyl or aryl, especially isopropyl.]

X

Formula II '

[In the above formula,

이다.]R is H or

to be.]

In another embodiment, the present invention comprises reacting a compound of formula II '' with H _{2 in} the presence of an acylating agent such as isobutyric anhydride or isobutyryl halide, more particularly isobutyric anhydride It provides a process for the preparation of compounds of:

(I)

Formula II '

Where

이다.R is H or

to be.

In another embodiment, the present invention comprises reacting a compound of formula II '' with H _{2 in} the presence of an acylating agent such as isobutyric anhydride or isobutyryl halide, more particularly isobutyric anhydride And a process for the preparation of a compound of formula

Formula I

X

Formula II ''

Where

이다.R is H or

to be.

In another embodiment, the invention provides acylating agents such as anhydride derivatives [((C ₁ -C ₈ ) alkyl) C (= 0)] ₂ O or [aryl (C = 0)] ₂ O, or halide derivatives ( Reacting a compound of formula (II) with H _{2 in} the presence of a (C ₁ -C ₈ ) alkyl) C (═O) halide or an aryl (C═O) halide and a heterogeneous transition metal hydrogenation catalyst Provided is a process for the preparation of a compound of formula (la). In particular, when the following R ¹ is isopropyl, the acylating agent is isobutyric anhydride or isobutyryl halide, in particular isobutyric anhydride:

Ia

[In the above formula,

R ¹ is (C ₁ -C ₈ ) alkyl or aryl, especially isopropyl.]

(II)

In another embodiment, the invention provides acylating agents such as anhydride derivatives [((C ₁ -C ₈ ) alkyl) C (= 0)] ₂ O or [aryl (C = 0)] ₂ O, or halide derivatives ( Reacting a compound of formula (II) with H _{2 in} the presence of a (C ₁ -C ₈ ) alkyl) C (═O) halide or an aryl (C═O) halide and a heterogeneous transition metal hydrogenation catalyst Provided is a process for the preparation of compounds of formula (la) and formula (X). In particular, when the following R ¹ is isopropyl, the acylating agent is isobutyric anhydride or isobutyryl halide, in particular isobutyric anhydride:

Ia

[In the above formula,

R ¹ is (C ₁ -C ₈ ) alkyl or aryl, especially isopropyl.]

X

(II)

In another embodiment, the present invention relates to a compound of formula I, comprising reacting a compound of formula II with H _{2 in} the presence of an acylating agent such as isobutyric anhydride or isobutyryl halide, in particular isobutyric anhydride Provide the manufacturing method:

Formula I

(II)

In another embodiment, the present invention comprises reacting a compound of formula (II) with H _{2 in} the presence of an acylating agent such as isobutyric anhydride or isobutyryl halide, in particular isobutyric anhydride, Provided are methods for preparing the compound of X:

Formula I

X

(II)

In certain embodiments, the present invention encompasses the formation of a compound of formula I ′, comprising forming a compound of formula I ′, comprising reacting a compound of formula II with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst. Provided are methods for preparing [[1- (2-ethylbutyl) -cyclohexyl] -carbonyl] amino) phenyl] 2-methylpropanethioate:

≪ RTI ID =

(II)

As described above, the present invention may be practiced in the presence of one solvent or a mixture of two or more solvents. In particular, the solvent may be an organic solvent such as an ether like solvent (eg tetrahydrofuran, methyltetrahydrofuran, diisopropyl ether, t-butylmethyl ether or dibutyl ether), an ester like solvent (eg ethyl acetate, iso Propyl acetate, butyl acetate), aliphatic hydrocarbon solvents (such as hexane, heptane or pentane), saturated alicyclic hydrocarbon solvents (such as cyclohexane or cyclopentane) or aromatic solvents (such as toluene, o-, m- or p- Xylene, or t-butyl-benzene) or mixtures thereof. In particular, the hydrogenation step according to the invention is carried out in the presence of a solvent selected from ether-like solvents, ester-like solvents, aliphatic hydrocarbon solvents, saturated cycloaliphatic hydrocarbon solvents or aromatic solvents or mixtures thereof, when no acylating agent is present, More particularly the solvent is an aliphatic hydrocarbon solvent, a saturated alicyclic hydrocarbon solvent or an aromatic solvent.

In another embodiment, the anhydride derivatives can act as solvents or co-solvents, for example in molar ratios of anhydrides / amidosulfides of 2-20, in particular 2-5.

In certain embodiments, the present invention provides a method as described above, wherein the acylating agent is isobutyric anhydride. In particular, 2.0-4.0 equivalents of isobutyric anhydride are used for the disulfide of formula II. More particularly, 2.5 to 3.5 equivalents are used.

In certain embodiments, the present invention provides a process as described above, wherein the reaction is carried out at a temperature of no greater than 150 ° C., in particular 25 ° C. to 150 ° C., more particularly 60 ° C. to 90 ° C., most particularly 80 ° C.

In certain embodiments, the present invention provides a method as described above, wherein H ₂ is added at a pressure of at least 0.1 bar, in particular from 0.1 to 100 bar, more particularly from 0.2 to 30 bar, most particularly from 5 to 25 bar. .

In certain embodiments, the invention relates to a nanoparticle palladium (0) (NP Pd (0), wherein the heterogeneous transition metal hydrogenation catalyst is microencapsulated in a Raney catalyst, Pd / C, Pd (OH) ₂ / C, polyurea matrix Encat (trademark) 30), Au / TiO ₂ , Rh / C, Ru / Al ₂ O _{3 ,} Ir / CaCO ₃ or Pt / C or mixtures thereof, in particular Raney catalyst, Pd / C, Pd (OH) ₂ / C, Au / TiO ₂ , Rh / C, Ru / Al ₂ O _3, Ir / CaCO ₃ or Pt / C or mixtures thereof, more particularly Pd / C, Pd (OH) ₂ / C, Au / TiO ₂ , Rh / C, Ra-Ni or Pt / C, most particularly Pd / It provides a method as described above which is C or Ra-Ni. Hydrogenation can proceed towards disulfide in the presence of molar excess of palladium. More suitably, palladium is used in an amount of 0.001 to 0.1 equivalents, preferably 0.01 to 0.1 equivalents, relative to the catalytic amount, such as disulfide. The catalyst can be reused many times if the molar ratio between the converted disulfide and the palladium used is correspondingly increased.

In another embodiment, the present invention provides a compound of Formula X:

X

In another embodiment, the present invention provides a compound of formula (I) comprising a compound of formula (X) and having less than 0.1% by weight of the compound of formula (X):

Formula I

X

In another embodiment, the present invention comprises a compound of formula X, having from 1 ppb (1 billion by weight) to 100 ppm (1 million by weight), in particular 1 ppb to 1 ppm of a compound of formula X There is provided a compound of formula I:

Formula I

X

Compounds of formula (I ′) and formula (X) may be prepared according to Scheme 1 of the conditions of the above described process:

[Reaction Scheme 1]

Compounds of formula (I) and formula (X) may be prepared according to Scheme 2 of the conditions of the above described process:

[Reaction Scheme 2]

Compounds of formulas II and II 'may be prepared according to Scheme 3:

Scheme 3

Where

X is I, Br, Cl or F.

In particular, the method comprises reacting a cyclohexanecarboxylic acid derivative of formula IV with a halogenating agent such as PX ₃ , PX ₅ , SOX ₂ or NCX, COX ₂ to obtain an acyl halide of formula III. The halogenation step is preferably carried out in the presence of tri- (C ₁ -C ₅ ) alkylamine. In addition, the reaction is carried out by reacting an acyl halide with bis (2-aminophenyl) disulfide in the presence of a base (e.g., N-methylmorpholine, di-N-methylpiperazine, pyridine). Acylation of the amino group of disulfide.

Starting materials, reagents and catalysts (synthetic routes of which are not explicitly disclosed herein) are generally readily available from commercial sources or are readily prepared using methods known to those skilled in the art. For example, compounds of Formulas II and IV are disclosed in Shinkai et al., J. Med. Chem. 43: 3566-3572 (2000)], International Patent Publication No. 2007/051714 or International Patent Publication No. 2008/074677.

The preparation of the compound of formula IV comprises the preparation of the cyclohexanecarbonitrile derivative of formula VI followed by a hydrolysis step such as the following technique and Scheme 4:

[Reaction Scheme 4]

Compounds of formula (VI) may be substituted by alkylating agents such as 1-halo-2-ethylbutane or 2-ethyl-1-butanol and Grignard reagents such as (C ₁ -C ₆ ) alkyl-magnesium- It can be prepared by reacting with a halide, phenyl-magnesium-halide, heteroaryl-magnesium-halide or (C ₃ -C ₆ ) cycloalkyl-magnesium-halide. In particular, the abovementioned coupling reaction is carried out in the presence of a secondary amine. In particular, the Grignard reagent is added to cyclohexanecarbonitrile, more particularly in the presence of a secondary amine, followed by the addition of an alkylating agent as mentioned above. In particular, the coupling reactions mentioned above are followed by quenching of inorganic acids such as hydrofluoric acid, hydrochloric acid, boric acid, acetic acid, formic acid, nitric acid, phosphoric acid or sulfuric acid, most particularly hydrochloric acid:

(VII)

Compounds of formula IV can be prepared by the following steps:

(a) hydrolyzing a cyclohexanecarbonitrile derivative of formula VI with H ₂ O in the presence of a strong acid or with an aqueous base to obtain a cyclohexanecarboxylic acid amide derivative of formula V; And

(VI)

(V)

(b) reacting the cyclohexanecarboxylic acid amide derivative with a nitrosylating agent to give a compound of formula IV.

The nitrosylating agent is in situ, such as H ₂ SO ₄ and nitrous acid (HNO ₂ ) or H ₂ SO ₃ / HNO ₃ or N ₂ O ₃ / H ₂ SO ₄ or HNO ₃ / SO ₂ by mixing nitrosulfonic acid (NOHSO Can be produced by obtaining ₄ ).

In another embodiment, the present invention provides a compound of formula (I) comprising a compound of formula (V) and having less than 0.1% by weight of the compound of formula (V):

Formula I

Formula V

In another embodiment, the present invention provides a compound of formula (I) comprising a compound of formula (V) and having from 1 ppm to 100 ppm, in particular 1 ppm to 1 ppm of a compound of formula (V):

Formula I

Formula V

In another embodiment, the present invention provides a compound of formula (I) comprising a compound of formula (X) and a compound of formula (V) having less than 0.1% by weight of a compound of formula (X) and less than 0.1% of a compound of formula (V) Provides compounds of:

Formula I

X

Formula V

In another embodiment, the present invention relates to a compound of formula (X) having 1ppb to 100ppm and 1ppb to 100ppm of a compound of formula (V), in particular 1ppb to 1ppm of a compound of formula (X) A compound of formula (I) comprising: a compound of formula (X) having a compound of formula (V)

Formula I

X

Formula V

In another embodiment, this invention relates to thiisobutyric acid S- (2-{[1- (2-ethyl-butyl) -cyclohexanecarbonyl] -amino} -phenyl) ester, S- [2-([[ Comprising a compound of formula (I) and a compound of formula (X), also known as 1- (2-ethylbutyl) -cyclohexyl] -carbonyl] amino) phenyl] 2-methylpropanethioate or dalcetrapib It provides a pharmaceutical composition. In particular, the composition comprises a compound of formula (I) and a compound of formula (X) of 1 ppb to 100 ppm, more particularly 1 ppb to 1 ppm.

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a compound of Formula (V). In particular, the composition comprises a compound of formula (I) and a compound of formula (V) of 1 ppb to 100 ppm, more particularly 1 ppb to 1 ppm.

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (X), and a compound of Formula (V). In particular, the composition comprises a compound of formula (I) and 1 ppb to 100 ppm of a compound of formula (X) and 1 ppb to 100 ppm of a compound of formula (V).

In general, the nomenclature used herein is based on the AUTONOM (trademark) 2000, a computational system of the Weilstein Institute for calculating IUPAC taxonomic nomenclature. The chemical structures presented herein are shown using MDL ISIS® version 2.5 SP2. Any open valency present on carbon, oxygen or nitrogen atoms in the structure herein indicates the presence of hydrogen atoms.

The following examples are provided for the purpose of further description and are not intended to limit the scope of the claimed invention.

The following abbreviations and definitions are used:

Ar: Argon

Acid chloride: 1- (2-ethyl-butyl) -cyclohexanecarbonyl chloride

Amidodisulfide: N, N '-(dithiodi-2,1-phenylene) bis [1- (2-ethylbutyl) -cyclohexanecarboxamide]

Amidothiophenol: 1- (2-ethylbutyl) -N- (2-mercaptophenyl) -cyclohexanecarboxamide

Thioester: S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

DTDA: 2,2`-dithiodianiline

d.i .: deionized

eq.:equivalent

EtOH: ethanol

g: grams

HPLC: High Performance Liquid Chromatography

GC: Gas Chromatography

h: hour

M: molarity [mole / L]

MeOH: methanol

ml: milliliters

RT: room temperature

The pressure specified in the experiment is the gauge pressure, that is, the pressure relative to the local atmospheric pressure.

Example 1: Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

A solution of amidodisulfide (12.9 mmol, 8.2 g) and isobutyric anhydride (38.7 mmol, 6.1 g) in toluene (16.9 g) was dissolved in Pd / C (519 μmol Pd, EVONIK E101 N / D 10%, 552 mg) was transferred to a 185 ml stainless steel autoclave, sealed and pressurized three times with 5 bar H ₂ and released to atmospheric pressure. The autoclave was heated to 80 ° C. under program control, after which 5 bars of H ₂ were charged. Hydrogenation was carried out at 80 ° C. and 5 bar (0.5 MPa) with vigorous stirring for 18 hours. The autoclave was then cooled to room temperature, depressurized and the reaction mixture was filtered. The filtrate was evaporated at 50 ° C./15 mbar and dissolved in EtOH (78 g). Di H ₂ O (22 g) was added under Ar at room temperature to give a precipitate of thioester (9.67 g) as white crystals having a melting point of 64.2 to 64.4 ° C. (yield 96.3%). The amount of 1- (2-ethylbutyl) -N- (2-mercaptophenyl) -cyclohexanecarboxamide observed was less than 0.5%.

Example 2: Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

This Example was carried out in a similar manner to Example 1, but 12.8 g of toluene was used. After workup and crystallization, thioester (9.63 g) as white crystals with 100% HPLC area% purity was isolated (yield 96%).

Example 3: Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

This example was carried out in a similar manner to Example 1 but using 26.7 g of toluene. After workup and crystallization, thioester (9.73 g) as white crystals with 100% HPLC area% purity was isolated (yield 97%).

Example 4: Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

Amidodisulfide (12.9 mmol, 8.2 g) and isobutyric anhydride (38.7 mmol, 6.1 g) in toluene (16.8 g) together with Pd / C (519 μmol Pd, Evonik E101 N / D 10%, 552 mg) Transferred to a stainless steel autoclave. It was hydrogenated with vigorous stirring at 90 ° C. and 5 bar (0.5 MPa) for 3 hours. Post-treatment according to example 1 gave thioester (9.63 g) as white crystals (yield 95.9%). HPLC analysis showed a purity of 100 area%.

Example 5: Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

This example was carried out in a similar manner to Example 1, but before being transferred to the autoclave, a Pd (OH) ₂ / C catalyst (519 μmol Pd, wet, about 50 weights, first washed three times with THF and then three times with toluene % H ₂ O, 552 mg) was used. The mixture was hydrogenated at 80 ° C. and 5 bar (0.5 MPa) with vigorous stirring for 5 hours. Post-treatment according to Example 1 recovered thioester (9.76 g) as white crystals (yield 97.2%). HPLC analysis showed a purity of 100 area%.

Example 6: Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

This example was carried out in a similar manner to Example 1 but using an nPdnAl ₂ O ₃ / Al ₂ O ₃ catalyst (519 μmol Pd, SDC materials, 1.15 g, 4.78%). The mixture was hydrogenated at 80 ° C. and 5 bar (0.5 MPa) with vigorous stirring for 5 hours. Post-treatment according to Example 1 recovered thioester (9.86 g) as white crystals (yield 98.2%). HPLC analysis showed a purity of 100 area%.

Example 7: Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

Amidodisulfide (12.9 mmol, 8.2 g) and isobutyric anhydride (38.7 mmol, 6.1 g) in toluene (16.8 g) together with Pd / C (519 μmol Pd, Evonik E101 N / D 10%, 552 mg) Transferred to a stainless steel autoclave. It was hydrogenated with vigorous stirring at 80 ° C. and 0.2 bar (0.02 MPa) for 18 hours. Post-treatment was carried out according to Example 1 to recover thioester (9.39 g) as white crystals (yield 93.5%). HPLC analysis showed a purity of 100 area%.

Example 8: Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

Amidodisulfide (12.9 mmol, 8.2 g) and isobutyric anhydride (38.7 mmol, 6.1 g) in ethyl acetate (16.8 g) with Pd / C (519 μmol Pd, Evonik E101 N / D 10%, 552 mg) Transfer to 185 ml stainless steel autoclave. The mixture was hydrogenated at 80 ° C. and 5 bar (0.5 MPa) with vigorous stirring for 18 hours. HPLC analysis showed complete conversion. Post-treatment according to Example 1 afforded thioester (8.54 g) as white crystals (yield 85.1%). HPLC analysis showed a purity of 100 area%.

Example 9: Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

This example was carried out in a similar manner to Example 8 but using tert-butyl methyl ether. It was hydrogenated with vigorous stirring at 80 ° C. and 5 bar (0.5 MPa) for 18 hours. HPLC analysis showed complete conversion. Post-treatment according to example 1 afforded thioester (8.98 g) as white crystals (yield 88.5%). HPLC analysis showed a purity of 100 area%.

Example 10 Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

Amidodisulfide (12.9 mmol, 8.2 g) and isobutyryl chloride (38.7 mmol, 4.2 g) in toluene (16.8 g) together with Pd / C (519 μmol Pd, Evonik E101 N / D 10%, 552 mg) Transfer to 185 ml stainless steel autoclave. The mixture was hydrogenated at 80 ° C. and 5 bar (0.5 MPa) with vigorous stirring for 18 hours. The reaction mixture was then analyzed by HPLC, showing 70.6% conversion of amidodisulfide and 52% thioester HPLC area percent. Further, 2.9 area% 1- (2-ethylbutyl) -N- (2-mercaptophenyl) -cyclohexanecarboxamide and 14.5 area% 2- [1- (2-ethyl-butyl) -cyclohexyl ] -Benzothiazole was formed.

Example 11: Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

This example was carried out in a similar manner to Example 10 except that isobutyric anhydride (4.1 g, 25.8 mmol, 2.0 equiv) was used as a reagent. The mixture was hydrogenated at 80 ° C. and 5 bar (0.5 MPa) with vigorous stirring for 18 hours. HPLC analysis showed complete conversion. Post-treatment according to Example 1 yielded thioester (7.05 g) as white crystals (yield 68.5%). HPLC analysis showed a purity of 100 area%.

Example 12 Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

Amidodisulfide (12.9 mmol, 8.2 g) in isobutyric anhydride (145 mmol, 22.9 g) was transferred to 185 ml stainless steel autoclave with Pd / C (519 μmol Pd, Evonik E101 N / D 10%, 552 mg). . The mixture was hydrogenated at 80 ° C. and 5 bar (0.5 MPa) with vigorous stirring for 18 hours. HPLC analysis showed complete conversion. Post-treatment according to example 1 gave thioester (9.57 g) as white crystals (yield 95.3%). HPLC analysis showed a purity of 100 area%.

Example 13: Synthesis of 1- (2-ethylbutyl) -N- (2-mercaptophenyl) -cyclohexanecarboxamide

Amidodisulfide (12.9 mmol, 8.2 g) in toluene (22.9 g) was transferred to 185 ml stainless steel autoclave with Pd / C (519 μmol Pd, Evonik E101 N / D 10%, 552 mg). It was hydrogenated with vigorous stirring at 80 ° C. and 10 bar (1.0 MPa) for 18 hours. The reaction mixture was then analyzed by HPLC, showing 100% conversion of amidodisulfide and 99.2% amidothiophenol HPLC area percent.

Example 14 Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

Amidodisulfide (12.9 mmol, 8.2 g) and isobutyric anhydride (38.7 mmol, 6.1 g) in toluene (16.8 g) together with Raney-Ni (2.59 mmol Ni, Evonik B113 Z 46.5%, 327 mg) were 185 ml. Transferred to stainless steel autoclave. It was hydrogenated with vigorous stirring at 100 ° C. and 1 bar (0.1 MPa) for 18 hours. The reaction mixture was then analyzed by HPLC, showing 100% conversion of amidodisulfide and 100% thioester.

Example 15 Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

Amidodisulfide (12.9 mmol, 8.2 g) and isobutyric anhydride (38.7 mmol, 6.1 g) in toluene (16.8 g) were microencapsulated nanoparticle palladium (0) (NP Pd (0) encats in a polyurea matrix. (Trademark) 30, commercially available from Sigma-Aldrich (registered trademark), (540 μmol Pd, 0.4 mmol Pd / g, 1.35 g) was transferred to a 185 ml stainless steel autoclave. It was hydrogenated with vigorous stirring at 90 ° C. and 30 bar (3 MPa) for 18 hours. The reaction mixture was then analyzed by HPLC, showing complete conversion of amidodisulfide and 100% of the desired product. The catalyst was reused for another 10 times under the same conditions, all showing the same result, ie complete conversion and 100% of the desired product.

Example 16: Synthesis of S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] -phenyl] 2-methylthiopropionate

In the table below, the reaction conditions are amidodisulfide (0.314 mmol) in toluene (410 mg), isobutyric anhydride (3 equiv), metal catalysts (catalysts specifically mentioned in the table below, 0.0403 equiv), 80 ° C., 5 bar The reaction was carried out according to the method similar to Example 1 having a reaction time of 18 hours. The reaction mixture was then analyzed by HPLC.

Claims (42)

A process for preparing a compound of formula I '', comprising reacting a compound of formula II '' with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst:
Formula I ''

[In the above formula,
X ¹ , X ² , X ³ and X ⁴ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH -C (= 0) R ^d or -NR ^e ₂ ;
Two adjacent substituents (ie, X ¹ and X ² , or X ² and X ³ , or X ³ and X ⁴ ) optionally include additional heteroatoms selected from O, NH and S together with the carbon atoms to which they are attached To form a 4, 5 or 6 membered cycloalkyl ring, wherein the above mentioned 4, 5 or 6 membered cycloalkyl ring is optionally substituted with 1 to 3 substituents independently selected from (C ₁ -C ₈ ) alkyl or aryl Become;
R ^a , R ^b , R ^c and R ^d are independently (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, aryl or heteroaryl;
Each R ^e is independently hydrogen, (C ₁ -C ₈ ) alkyl or aryl.]
Formula II ''

[In the above formula,
X ^{1 ′} , X ^{2 ′} , X ^{3 ′} and X ^{4 ′} are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH-C (= 0) R ^d or -NR ^e ₂ ;
Two adjacent substituents (ie, X ^{1 ′} and X ^{2 ′} , or X ^{2 ′} and X ^{3 ′} , or X ^{3 ′} and X ^{4 ′} ) together with the carbon atoms to which they are attached are further selected from O, NH and S To form a 4, 5 or 6 membered cycloalkyl ring optionally containing heteroatoms, wherein the above mentioned 4, 5 or 6 membered cycloalkyl ring is selected from 1 to 3 independently selected from (C ₁ -C ₈ ) alkyl or aryl Optionally substituted with 4 substituents;
R ^a , R ^b , R ^c , R ^d , R ^e , X ¹ , X ² , X ³ and X ⁴ are as defined above.] The method of claim 1,
Acylating agents such as anhydride derivatives [((C ₁ -C ₈ ) alkyl) C (═O)] ₂ O or [aryl (C═O)] ₂ O, or halide derivatives ((C ₁ -C ₈ ) alkyl) A compound of formula I '''comprising reacting a compound of formula II''with H _{2 in} the presence of a C (= 0) halide or an aryl (C = 0) halide and a heterogeneous transition metal hydrogenation catalyst Manufacturing method:
Formula I '''

[In the above formula,
X ¹ , X ² , X ³ and X ⁴ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH -C (= 0) R ^d or -NR ^e ₂ ;
Two adjacent substituents (ie, X ¹ and X ² , or X ² and X ³ , or X ³ and X ⁴ ) optionally include additional heteroatoms selected from O, NH and S together with the carbon atoms to which they are attached To form a 4, 5 or 6 membered cycloalkyl ring, wherein the above mentioned 4, 5 or 6 membered ring is optionally substituted with 1 to 3 substituents independently selected from (C ₁ -C ₈ ) alkyl or aryl;
R ¹ is (C ₁ -C ₈ ) alkyl or aryl;
R ^a , R ^b , R ^c and R ^d are independently (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, aryl or heteroaryl;
Each R ^e is independently hydrogen, (C ₁ -C ₈ ) alkyl or aryl.]
Formula II ''

[In the above formula,
X ^{1 ′} , X ^{2 ′} , X ^{3 ′} and X ^{4 ′} are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH-C (= 0) R ^d or -NR ^e ₂ ;
Two adjacent substituents (ie, X ^{1 ′} and X ^{2 ′} , or X ^{2 ′} and X ^{3 ′} , or X ^{3 ′} and X ^{4 ′} ) together with the carbon atoms to which they are attached are further selected from O, NH and S To form a 4, 5 or 6 membered cycloalkyl ring optionally containing heteroatoms, wherein the above mentioned 4, 5 or 6 membered cycloalkyl ring is selected from 1 to 3 independently selected from (C ₁ -C ₈ ) alkyl or aryl Optionally substituted with 4 substituents;
R ^a , R ^b , R ^c , R ^d , R ^e , X ¹ , X ² , X ³ and X ⁴ are as defined above.] The method of claim 1,
A process for preparing a compound of formula I '', comprising reacting a compound of formula II '' with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst:
Formula I ''

[In the above formula,
X ¹ is -NH-C (= O) R d, wherein R ^d is (C ₁ -C ₈₎ alkyl substituted with (C ₃ -C ₈₎ cycloalkyl;
X ² , X ³ and X ⁴ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH-C ( ═O) R ^d or —NR ^e ₂ ;
R ^a , R ^b , R ^c and R ^d are independently (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, aryl or heteroaryl;
Each R ^e is independently hydrogen, (C ₁ -C ₈ ) alkyl or aryl.]
Formula II ''

[In the above formula,
X ^{1 '} is -NH-C (= 0) R ^d or -NR ^e' ₂ ;
R ^d is (C ₁ -C ₈₎ alkyl substituted with (C ₃ -C ₈₎ cycloalkyl;
R ^{e '} is hydrogen;
X ^{2 '} , X ^3' and X ^{4 '} are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH -C (= 0) R ^d or -NR ^e ₂ ;
R ^a , R ^b , R ^c , R ^d , R ^e , X ¹ , X ² , X ³ and X ⁴ are as defined above.] 3. The method of claim 2,
A process for preparing a compound of formula I '''comprising reacting a compound of formula II''with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst:
Formula I '''

[In the above formula,
X ¹ is -NH-C (= O) R d, wherein R ^d is (C ₁ -C ₈₎ alkyl substituted with (C ₃ -C ₈₎ cycloalkyl;
X ² , X ³ and X ⁴ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH-C ( ═O) R ^d or —NR ^e ₂ ;
R ^a , R ^b , R ^c and R ^d are independently (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, aryl or heteroaryl;
Each R ^e is independently hydrogen, (C ₁ -C ₈ ) alkyl or aryl;
R ¹ is (C ₁ -C ₈ ) alkyl or aryl.]
Formula II ''

[In the above formula,
X ^{1 '} is -NH-C (= 0) R ^d or -NR ^e' ₂ ;
R ^d is (C ₁ -C ₈₎ alkyl substituted with (C ₃ -C ₈₎ cycloalkyl;
R ^{e '} is hydrogen;
X ^{2 '} , X ^3' and X ^{4 '} are each independently hydrogen, (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, -OR ^a , -OC (= 0) R ^b , -NHR ^c , -NH -C (= 0) R ^d or -NR ^e ₂ ;
R ^a , R ^b , R ^c , R ^d , R ^e , X ¹ , X ² , X ³ and X ⁴ are as defined above.] 5. The method according to any one of claims 1 to 4,
R ^d is (2-ethyl-butyl) -cyclohexyl. 6. The method according to any one of claims 1 to 5,
X ² , X ³ and X ⁴ are each independently hydrogen or (C ₁ -C ₈ ) alkyl. 7. The method according to any one of claims 1 to 6,
X ^{2 '} , X ^3' and X ^{4 '} are each independently hydrogen or (C ₁ -C ₈ ) alkyl. The method according to any one of claims 1, 3, 5 and 6,
A process for preparing a compound of formula (I ′) comprising reacting a compound of formula (II ′) with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst:
≪ RTI ID =

Formula II ''

In this formula,
R is H or

to be. The method according to any one of claims 1, 3, 5, 6 and 8,
A process for preparing a compound of formula (I ') and (X) comprising reacting a compound of formula (II') with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst:
≪ RTI ID =

X

≪ RTI ID =

In this formula,
R is H or

to be. The method according to any one of claims 2, 4, 5 and 6,
Acylating agents such as anhydride derivatives [((C ₁ -C ₈ ) alkyl) C (═O)] ₂ O or [aryl (C═O)] ₂ O, or halide derivatives ((C ₁ -C ₈ ) alkyl) A process for preparing a compound of formula (Ia) comprising reacting a compound of formula (II ′) with H _{2 in} the presence of a C (═O) halide or an aryl (C═O) halide and a heterogeneous transition metal hydrogenation catalyst:
Ia

[In the above formula,
R ¹ is (C ₁ -C ₈ ) alkyl or aryl, especially isopropyl.]
≪ RTI ID =

[In the above formula,
R is H or

to be.] The method according to any one of claims 2, 4, 5, 6 and 10,
Acylating agents such as anhydride derivatives [((C ₁ -C ₈ ) alkyl) C (═O)] ₂ O or [aryl (C═O)] ₂ O, or halide derivatives ((C ₁ -C ₈ ) alkyl) A compound of formula (la) and (X) comprising reacting a compound of formula (II ′) with H _{2 in} the presence of a C (═O) halide or an aryl (C═O) halide and a heterogeneous transition metal hydrogenation catalyst Manufacturing method:
Ia

[In the above formula,
R ¹ is (C ₁ -C ₈ ) alkyl or aryl, especially isopropyl.]
X

≪ RTI ID =

[In the above formula,
R is H or

to be.] The method according to any one of claims 8 to 11,
R is

/ RTI > The method according to any one of claims 2, 4 to 7, and 10 to 12,
R ¹ is isopropyl and the acylating agent is isobutyric anhydride or isobutyryl halide. The method according to any one of claims 2, 4 to 7, and 10 to 13,
The acylating agent is isobutyric anhydride. The method according to any one of claims 2, 4 to 7, and 10 to 14,
A process wherein from 2.0 to 4.0 equivalents of isobutyric anhydride is used relative to the disulfide of formula II. 16. The method according to any one of claims 1 to 15,
The process is carried out in the presence of one solvent or a mixture of two or more solvents. 17. The method according to any one of claims 1 to 16,
The solvent is an organic solvent. 18. The method according to any one of claims 1 to 17,
The solvent is an ether-like solvent, an ester-like solvent, an aliphatic hydrocarbon solvent, a saturated alicyclic hydrocarbon solvent or an aromatic solvent or mixtures thereof. The method according to any one of claims 1, 3 and 5 to 9,
The solvent is selected from ether-like solvents, ester-like solvents, aliphatic hydrocarbon solvents, saturated alicyclic hydrocarbon solvents or aromatic solvents or mixtures thereof. The method of claim 19,
The solvent is an aliphatic hydrocarbon solvent, a saturated alicyclic hydrocarbon solvent or an aromatic solvent. The method according to any one of claims 2, 4 to 7, and 10 to 18,
Anhydride derivatives can act as solvents or co-solvents having an anhydride / amidodisulfide molar ratio of 2 to 20. S- [2-([[1- (2-ethyl, comprising the formation of a compound of formula (I ') comprising reacting a compound of formula (II) with H _{2 in} the presence of a heterogeneous transition metal hydrogenation catalyst Butyl) -cyclohexyl] -carbonyl] amino) phenyl] 2-methylpropanethioate
≪ RTI ID =

(II)

The method according to any one of claims 1 to 22,
H ₂ is added at a pressure of at least 0.1 bar, in particular from 0.1 to 100 bar, more particularly from 0.2 to 30 bar, most particularly from 5 to 25 bar. 24. The method according to any one of claims 1 to 23,
The reaction is carried out at a temperature of at most 150 ° C, in particular 25 ° C to 150 ° C, more particularly at 60 ° C to 90 ° C and most particularly at 80 ° C. The method according to any one of claims 1 to 24,
Heterogeneous transition metal hydrogenation catalysts include Raney catalyst, Pd / C, Pd (OH) ₂ / C, nanoparticles palladium (0) microencapsulated in polyurea matrix, Au / TiO ₂ , Rh / C, Ru / Al ₂ O _3, Ir / CaCO ₃ , Pt / C or mixtures thereof. The method according to any one of claims 1 to 25,
Heterogeneous transition metal hydrogenation catalysts include Raney catalysts, Pd / C, Pd (OH) ₂ / C, Au / TiO ₂ , Rh / C, Ru / Al ₂ O _{3 ,} Ir / CaCO ₃ , Pt / C or their Method of mixture. The method according to any one of claims 1 to 26,
Wherein the heterogeneous transition metal hydrogenation catalyst is Pd / C, Pd (OH) ₂ / C, Au / TiO ₂ , Rh / C, Ra-Ni or Pt / C. The method according to any one of claims 1 to 27,
Wherein the heterogeneous transition metal hydrogenation catalyst is Pd / C or Ra-Ni. A compound of formula
X

A compound of formula (I) comprising a compound of formula (X) and having less than 0.1% by weight of the compound of formula (X):
Formula I

X

30. The method of claim 29,
A compound of formula (I) comprising a compound of formula (X) and having from 1 ppb to 100 ppm, in particular from 1 ppb to 1 ppm of a compound of formula (X):
Formula I

X

A compound of formula (I) comprising a compound of formula (V) and having less than 0.1% by weight of the compound of formula (V):
Formula I

Formula V

The method of claim 31, wherein
A compound of formula (I) comprising a compound of formula (V) and having from 1 ppb to 100 ppm, in particular 1 ppb to 1 ppm of a compound of formula (V):
Formula I

Formula V

32. The method of claim 29 or 31,
A compound of formula (I) comprising: a compound of formula (X) having less than 0.1% of a compound of formula (X) by weight and less than 0.1% of a compound of formula (V):
Formula I

X

Formula V

33. The method of claim 32,
Compounds of formula (X) having from 1ppb to 100ppm of a compound of formula (X) and from 1ppb to 100ppm of a compound of formula (V), in particular from 1ppb to 1ppm of a compound of formula (X) and from 1ppb to 1ppm of a compound of formula (V) A compound of formula I, comprising a compound of V:
Formula I

X

Formula V

A pharmaceutical composition comprising S- [2-([[1- (2-ethylbutyl) -cyclohexyl] -carbonyl] amino) phenyl] 2-methylpropanethioate and a compound of formula (X). The method of claim 36,
A pharmaceutical composition comprising 1 ppm to 100 ppm, more particularly 1 ppm to 1 ppm of a compound of formula X. A pharmaceutical composition comprising S- [2-([[1- (2-ethylbutyl) -cyclohexyl] -carbonyl] amino) phenyl] 2-methylpropanethioate and a compound of formula (V). 39. The method of claim 37,
A pharmaceutical composition comprising 1 ppb to 100 ppm, more particularly 1 ppb to 1 ppm of a compound of formula (V). The method according to any one of claims 36 to 39, wherein
A pharmaceutical composition comprising S- [2-([[1- (2-ethylbutyl) -cyclohexyl] -carbonyl] amino) phenyl] 2-methylpropanethioate, a compound of Formula X and a compound of Formula V . 41. The method of any of claims 36-40, wherein
S- [2-([[1- (2-ethylbutyl) -cyclohexyl] -carbonyl] amino) phenyl] 2-methylpropanethioate, 1 ppb to 100 ppm of compound of formula X and 1 ppb to 100 ppm of formula V A pharmaceutical composition comprising a compound of. Invention as described above.